Integrin α6β4 Confers Doxorubicin Resistance in Cancer Cells by Suppressing Caspase-3–Mediated Apoptosis: Involvement of N-Glycans on β4 Integrin Subunit
Drug resistance is a major obstacle to successful cancer treatment. Therefore, it is essential to understand the molecular mechanisms underlying drug resistance to develop successful therapeutic strategies. α6β4 integrin confers resistance to apoptosis and regulates the survival of cancer cells; how...
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| Format: | Article |
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MDPI AG
2023-12-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/12/1752 |
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| author | Yoshinobu Kariya Jianguo Gu Yukiko Kariya |
| author_facet | Yoshinobu Kariya Jianguo Gu Yukiko Kariya |
| author_sort | Yoshinobu Kariya |
| collection | DOAJ |
| description | Drug resistance is a major obstacle to successful cancer treatment. Therefore, it is essential to understand the molecular mechanisms underlying drug resistance to develop successful therapeutic strategies. α6β4 integrin confers resistance to apoptosis and regulates the survival of cancer cells; however, it remains unclear whether α6β4 integrin is directly involved in chemoresistance. Here, we show that α6β4 integrin promotes doxorubicin resistance by decreasing caspase-3–mediated apoptosis. We found that the overexpression of α6β4 integrin by the β4 integrin gene rendered MDA-MB435S and Panc-1 cells more resistant to doxorubicin than control cells. The acquired resistance to doxorubicin by α6β4 integrin expression was abolished by the deletion of the cytoplasmic signal domain in β4 integrin. Similar results were found in MDA-MB435S and Panc-1 cells when N-glycan-defective β4 integrin mutants were overexpressed or bisecting GlcNAc residues were increased on β4 integrin by the co-expression of N-acetylglucosaminyltransferase III with β4 integrin. The abrogation of α6β4 integrin-mediated resistance to doxorubicin was accompanied by reduced cell viability and an increased caspase-3 activation. Taken together, our results clearly suggest that α6β4 integrin signaling plays a key role in the doxorubicin resistance of cancer cells, and N-glycans on β4 integrin are involved in the regulation of cancer cells. |
| first_indexed | 2024-03-08T20:57:38Z |
| format | Article |
| id | doaj.art-57208de81f9045238e71e8b04efe69e9 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-08T20:57:38Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-57208de81f9045238e71e8b04efe69e92023-12-22T13:56:00ZengMDPI AGBiomolecules2218-273X2023-12-011312175210.3390/biom13121752Integrin α6β4 Confers Doxorubicin Resistance in Cancer Cells by Suppressing Caspase-3–Mediated Apoptosis: Involvement of N-Glycans on β4 Integrin SubunitYoshinobu Kariya0Jianguo Gu1Yukiko Kariya2Department of Biochemistry, Fukushima Medical University, Fukushima City 960-1295, JapanDivision of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Komatsushima 981-8558, JapanMedical-Industrial Translational Research Center, Fukushima Medical University, Fukushima City 960-1295, JapanDrug resistance is a major obstacle to successful cancer treatment. Therefore, it is essential to understand the molecular mechanisms underlying drug resistance to develop successful therapeutic strategies. α6β4 integrin confers resistance to apoptosis and regulates the survival of cancer cells; however, it remains unclear whether α6β4 integrin is directly involved in chemoresistance. Here, we show that α6β4 integrin promotes doxorubicin resistance by decreasing caspase-3–mediated apoptosis. We found that the overexpression of α6β4 integrin by the β4 integrin gene rendered MDA-MB435S and Panc-1 cells more resistant to doxorubicin than control cells. The acquired resistance to doxorubicin by α6β4 integrin expression was abolished by the deletion of the cytoplasmic signal domain in β4 integrin. Similar results were found in MDA-MB435S and Panc-1 cells when N-glycan-defective β4 integrin mutants were overexpressed or bisecting GlcNAc residues were increased on β4 integrin by the co-expression of N-acetylglucosaminyltransferase III with β4 integrin. The abrogation of α6β4 integrin-mediated resistance to doxorubicin was accompanied by reduced cell viability and an increased caspase-3 activation. Taken together, our results clearly suggest that α6β4 integrin signaling plays a key role in the doxorubicin resistance of cancer cells, and N-glycans on β4 integrin are involved in the regulation of cancer cells.https://www.mdpi.com/2218-273X/13/12/1752α6β4 integrindoxorubicinchemoresistancecaspase-3N-acetylglucosaminyltransferase III (GnT-III)bisecting GlcNAc |
| spellingShingle | Yoshinobu Kariya Jianguo Gu Yukiko Kariya Integrin α6β4 Confers Doxorubicin Resistance in Cancer Cells by Suppressing Caspase-3–Mediated Apoptosis: Involvement of N-Glycans on β4 Integrin Subunit Biomolecules α6β4 integrin doxorubicin chemoresistance caspase-3 N-acetylglucosaminyltransferase III (GnT-III) bisecting GlcNAc |
| title | Integrin α6β4 Confers Doxorubicin Resistance in Cancer Cells by Suppressing Caspase-3–Mediated Apoptosis: Involvement of N-Glycans on β4 Integrin Subunit |
| title_full | Integrin α6β4 Confers Doxorubicin Resistance in Cancer Cells by Suppressing Caspase-3–Mediated Apoptosis: Involvement of N-Glycans on β4 Integrin Subunit |
| title_fullStr | Integrin α6β4 Confers Doxorubicin Resistance in Cancer Cells by Suppressing Caspase-3–Mediated Apoptosis: Involvement of N-Glycans on β4 Integrin Subunit |
| title_full_unstemmed | Integrin α6β4 Confers Doxorubicin Resistance in Cancer Cells by Suppressing Caspase-3–Mediated Apoptosis: Involvement of N-Glycans on β4 Integrin Subunit |
| title_short | Integrin α6β4 Confers Doxorubicin Resistance in Cancer Cells by Suppressing Caspase-3–Mediated Apoptosis: Involvement of N-Glycans on β4 Integrin Subunit |
| title_sort | integrin α6β4 confers doxorubicin resistance in cancer cells by suppressing caspase 3 mediated apoptosis involvement of n glycans on β4 integrin subunit |
| topic | α6β4 integrin doxorubicin chemoresistance caspase-3 N-acetylglucosaminyltransferase III (GnT-III) bisecting GlcNAc |
| url | https://www.mdpi.com/2218-273X/13/12/1752 |
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